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that the ratio of the

patient’s body weight in kilograms to his or her height in meters squared (W/H2) is the most useful and

reproducible measure. This ratio is referred to as the body mass index (BMI). Normal men and women

fall into the range of 18.5 to 25. Percy’s current value is 21.3 and rising.

It is estimated that >30% of adults in the United States have a BMI >30, with >60% exhibiting a BMI

>25. For individuals with a BMI >27, which is quite close to a weight 20% above the “ideal” or

desirable weight, an attempt at weight loss should be strongly advised. The idea that obesity is a benign

condition unless it is accompanied by other risk factors for cardiovascular disease is disputed by several

long-term, properly controlled prospective studies. These studies show that obesity is an independent risk

factor not only for heart attacks and strokes, but for the development of insulin resistance, type 2 diabetes

mellitus, hypertension, and gallbladder disease.

Percy did not want to become overweight and decided to follow his new diet faithfully.

Cora N. Because Cora N.’s lipid profile indicated an elevation in both serum triacylglycerols and

LDL cholesterol, she was classified as having a combined hyperlipidemia. The dissimilarities in

the lipid profiles of Cora and her two siblings, both of whom were experiencing anginal chest pain, are

characteristic of the multigenic syndrome referred to as familial combined hyperlipidemia (FCH).

Approximately 1% of the North American population has FCH. It is the most common cause of

coronary artery disease in the United States. In contrast to patients with familial hypercholesterolemia

(FH), patients with FCH do not have fatty deposits within the skin or tendons (xanthomas) (see Chapter

32). In FCH, coronary artery disease usually appears by the fifth decade of life. Treatment of FCH includes restriction of dietary fat. Patients who do not respond adequately to

dietary therapy are treated with antilipidemic drugs. Selection of the appropriate antilipidemic drugs

depends on the specific phenotypic expression of the patients’ multigenic disease as manifest by theirparticular serum lipid profile. In Cora’s case, a decrease in both serum triacylglycerols and LDL

cholesterol must be achieved.

Because Cora has known coronary artery disease, she was prescribed a high-dose statin

(atorvastatin). Treatment of hypercholesterolemia is based on overall risk of cardiovascular disease.

Nicotinic acid (niacin) could also potentially be used to treat patients with hyperlipidemia because these

agents have the potential to lower serum triacylglycerol levels and cause a reciprocal rise in serum HDL

cholesterol levels as well as lowering serum total and LDL cholesterol levels. The mechanisms suggested

for niacin’s triacylglycerol-lowering action include enhancement of the action of LPL, inhibition of

lipolysis in adipose tissue, and a decrease in esterification of triacylglycerols in the liver (see Chapter

32, Table 32.6). The mechanism by which niacin lowers the serum total and LDL cholesterol levels is

related to the decrease in hepatic production of VLDL. When the level of VLDL in the circulation

decreases, the production of its daughter particles, IDL and LDL, also decreases. Niacin’s side effects of

flushing and itching are often found to be intolerable.

Statins, such as atorvastatin, inhibit cholesterol synthesis by inhibiting the activity of

hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the pathway (see

Chapter 32). After 3 months of therapy, atorvastatin decreased Cora’s LDL cholesterol from a

pretreatment level of 175 mg/dL to 122 mg/dL. Her fasting serum triacylglycerol concentration was

decreased from a pretreatment level of 280 mg/dL to 178 mg/dL.

Cora was also told to take 81 mg of aspirin every day. In the presence of aspirin, cyclooxygenase is

irreversibly inactivated by acetylation. New cyclooxygenase molecules are not produced in platelets

because platelets have no nuclei and, therefore, cannot synthesize new mRNA. Thus, the inhibition of

cyclooxygenase by aspirin persists for the lifespan of the platelet (7 to 10 days). When aspirin is taken

daily at doses between 81 and 325 mg, new platelets are affected as they are generated. Higher doses do

not improve efficacy but do increase side effects, such as gastrointestinal bleeding and easy bruisability.

Patients with established or suspected atherosclerotic coronary disease, such as Anne J., Cora N.,

and Ivan A., benefit from the action of low-dose aspirin (~81 mg/day), which produces a mild defect in

hemostasis. This action of aspirin helps to prevent thrombus formation in the area of an atherosclerotic

plaque at critical sites in the vascular tree.

Christy L. suffered from RDS, which is a major cause of death in the newborn. RDS is preventable

if prematurity can be avoided by appropriate management of high-risk pregnancy and labor. Before

delivery, the obstetrician must attempt to predict and possibly treat pulmonary prematurity in utero. For

example, estimation of fetal head circumference by ultrasonography, monitoring for fetal arterial oxygen

saturation, and determination of the ratio of the concentrations of phosphatidylcholine (lecithin) and that

of sphingomyelin in the amniotic fluid may help to identify premature infants who are predisposed to RDS

(Fig. 31.35).The administration of synthetic corticosteroids to women at risk of preterm birth can reduce the

incidence or mortality of RDS by stimulating fetal synthesis of lung surfactant. They are given to women

who are between 24 and 34 weeks pregnant and at risk of delivering within 7 days. The administration of one dose of surfactant into the trachea of the premature infant immediately after

birth, for babies with very poor respiratory function, can improve morbidity and mortality. In Christy’s

case, intensive therapy allowed her to survive this acute respiratory complication of prematurity.

BIOCHEM ICAL COM M ENTS

Metabolic Syndrome. Obesity is a relatively modern problem brought about by an excess of

nutrients and reduced physical activity. As individuals become obese, adipocyte function, in terms

of its biochemical and endocrine roles, is altered. Adiponectin levels fall, and with it, reduced fatty acid

oxidation occurs in tissues. The release of free fatty acids is also increased in large adipocytes,

presumably because of the high concentration of substrate (triglyceride), even if HSLis not activated.

This is coupled with a deficiency of perilipins in obese individuals. Perilipins are adipocyte

phosphoproteins that bind to triacylglycerol droplets and regulate the accessibility

of the triglyceride to

the lipases. A decrease in perilipin synthesis leads to an enhanced basal rate of lipolysis.

Fat cells begin to proliferate early in life, starting in the third trimester of gestation. Proliferation

essentially ceases before puberty, and thereafter, fat cells change mainly in size. However, some increase

in the number of fat cells can occur in adulthood if preadipocytes are induced to proliferate by growth

factors and changes in the nutritional state. Weight reduction results in a decrease in the size of fat cells

rather than a decrease in number. After weight loss, the amount of LPL, an enzyme involved in the transfer

of fatty acids from blood triacylglycerols to the triacylglycerol stores of adipocytes, increases. In

addition, the amount of mRNA for LPLalso increases. All of these factors suggest that individuals who

become obese, particularly those who do so early in life, will have difficulty losing weight and

maintaining a lower body adipose mass.

Signals that initiate or inhibit feeding are extremely complex and include psychological and hormonal

factors as well as neurotransmitter activity. These signals are integrated and relayed through the

hypothalamus. Destruction of specific regions of the hypothalamus can lead to overeating and obesity orto anorexia and weight loss. Overeating and obesity are associated with damage to the ventromedial or

the paraventricular nucleus, whereas weight loss and anorexia are related to damage to more lateral

hypothalamic regions. Compounds that act as satiety signals have been identified in brain tissue and

include leptin and glucagonlike peptide-1 (GLP-1). Appetite suppressors developed from compounds

such as these may be used in the future for the treatment of obesity. Increased circulating levels of nonesterified (or free) fatty acids (NEFA) are observed in obesity and

are associated with insulin resistance. Insulin resistance is also a hallmark of type 2 diabetes. There are

several theories as to why increased NEFA promote insulin resistance. One will be presented here, along

with the effects of NEFA on insulin release from the pancreas. As NEFA levels in the circulation rise,

muscle begins to use predominantly NEFA as an energy source. This reduces muscle glucose metabolism,

as a result of the buildup of acetyl-CoA in the mitochondria, export of citrate to the cytoplasm, and

inhibition of phosphofructokinase-1. Because glucose is not being metabolized, its uptake by muscle is

reduced. Because muscle is the predominant tissue that takes up glucose in response to insulin, impaired

glucose uptake (resulting from fat oxidation) is manifest as a sign of insulin resistance. NEFA are also

postulated to interfere with pancreatic β-cell secretion of insulin, further contributing to insulin resistance

(see the following for more on this topic).

Obesity, insulin resistance, and altered blood lipid levels are the start of a syndrome known as

metabolic syndrome. The metabolic syndrome commonly is diagnosed mostly based on criteria from the

International Diabetes Federation (IDF) Task Force on Epidemiology and Prevention and the American

Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI). For a diagnosis of metabolic

syndrome, at least three of the following components should be evident: Increased waist circumference: 40 inches or more for men, 35 inches or more for

woman

Elevated triglycerides (≥150 mg/dL)

Reduced HDL (<40 mg/dL for men, <50 mg/dLfor women) Elevated blood pressure (≥130/85 mm Hg)

Elevated fasting glucose (≥100 mg/dL)

Individuals with metabolic syndrome are at increased risk for type 2 diabetes and cardiovascular

disease. Treatment, in addition to lifestyle changes to reduce weight, increase exercise, and change diet,

will be discussed further in Chapter 32.

A characteristic of the metabolic syndrome is insulin resistance. Part of this resistance is caused by

altered insulin release from the β-cells of the pancreas under hyperlipidemic conditions. To understand

how this occurs, it is necessary to revisit normal glucose-stimulated insulin secretion (see Fig. 19.11).

Glucose is metabolized in the pancreatic β-cell to generate ATP, which closes ATP-sensitive K+

channels, which leads to a membrane depolarization, which activates voltage-gated Ca2+ channels in the

membrane. The corresponding increase in intracellular calcium levels leads to stimulation of the

exocytosis of insulin-containing vesicles. However, the process is more complicated than this and is

coupled to pyruvate cycling within the β-cell and the generation of NADPH. The exact role of NADPH in

stimulating insulin release has not yet been elucidated.

Islet cells express pyruvate carboxylase but very low levels of phosphoenolpyruvate carboxykinase.

As seen in Figure 31.36, NADPH is generated in the cytosol of the islet cells by malic enzyme and thecytosolic isozyme of isocitrate dehydrogenase, which uses NADP+ instead of NAD+ as the mitochondrial

enzyme does.

Thus, under normal conditions, glucose is metabolized to pyruvate, and the pyruvate enters the

mitochondria. Some of the pyruvate is converted to acetyl-CoA to generate energy; some of the pyruvate

is converted to OAA. The OAA generated can be converted to malate and exported to the cytoplasm,

where it is recycled to pyruvate by malic enzyme, generating NADPH. Alternatively, the OAA and acetylCoA generated within the mitochondria can condense and form citrate, isocitrate, and α-ketoglutarate, all

of which can leave the mitochondria and enter the cytosol. Cytosolic isocitrate is oxidized to α-

ketoglutarate, generating NADPH. Cytosolic citrate is split by citrate lyase to acetyl-CoA and OAA, and

the OAA is reduced to malate and cycled to pyruvate, generating more NADPH. The cytosolic acetyl-CoA

is used for limited fatty acid production in the islet cell. The elevated cytosolic NADPH then aids, in an

unknown manner, in the release of insulin from the β-cell.

So what goes wrong when β-cells are chronically exposed to high levels of NEFA in the circulation?

The β-cell begins to oxidize the fatty acids, which dramatically raises the acetyl-CoA levels in the β-cell

mitochondria. This leads to the activation of pyruvate carboxylase and enhanced pyruvate cycling, with

significant increases in resting NADPH levels. This, then, leads to blunted increases in NADPH levels

when glucose levels increase, as pyruvate cycling is already maximal because of the activation of

pyruvate carboxylase. Thus, the β-cell releases less insulin in response to the increase in blood glucose

levels, thereby contributing further to hyperglycemia that was initiated by the resistance to insulin’s action

in peripheral tissues. KEY CONCEPTS

Fatty acids are synthesized mainly in the liver, primarily from glucose.

Glucose is converted to pyruvate via glycolysis, which enters the mitochondrion and forms both

acetyl-CoA and OAA, which then forms citrate.The newly synthesized citrate is transported to the cytosol, where it is cleaved to form acetyl-CoA,

which is the source of carbons for fatty acid biosynthesis.

Two enzymes, acetyl-CoA carboxylase (the key regulatory step) and fatty acid synthase, produce

palmitic acid (16 carbons, no double bonds) from acetyl-CoA. After activation to palmitoyl-CoA,

the fatty acid can be elongated or desaturated (adding double bonds) by enzymes in the endoplasmic

reticulum.

The eicosanoids (prostaglandins, thromboxanes and leukotrienes) are potent regulators of

cellular function (such as the inflammatory response, smooth muscle contraction, blood pressure

regulation, and bronchoconstriction and bronchodilation) and are derived from polyunsaturated

fatty acids containing 20 carbon atoms.

The prostaglandins and thromboxanes require cyclooxygenase activity to be synthesized, whereas

the leukotrienes require lipoxygenase activity.

Cyclooxygenase is the target of nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin,

which covalently acetylates and inactivates the enzyme in platelets. Fatty acids are used to produce triacylglycerols (for energy storage) and glycerophospholipids and

sphingolipids (for structural components of cell membranes).

Liver-derived triacylglycerol is packaged with various apolipoproteins and secreted into the

circulation as very-low-density lipoprotein (VLDL).

As with dietary chylomicrons, lipoprotein lipase in the capillaries of adipose tissue, muscle, and the

lactating mammary gland digests the triacylglycerol of VLDL, forming fatty acids and glycerol.

Glycerophospholipids, synthesized from fatty acyl-CoA and glycerol 3-P, are all derived from

phosphatidic acid. Various head groups are added to phosphatidic acid to form the mature

glycerophospholipids.

Phospholipid degradation is catalyzed by phospholipases.

Sphingolipids are synthesized from sphingosine, which is derived from palmitoyl-CoA and serine.

Glycolipids, such as cerebrosides, globosides, and gangliosides, are sphingolipids. The sole sphingosine-based phospholipid is sphingomyelin.

The adipocyte is an active endocrine organ, producing adipokines that help to regulate appetite and

adipocyte size.

Metabolic syndrome refers to a clustering of a variety of metabolic abnormalities that together

dramatically increase the risk of type 2 diabetes and cardiovascular disease. Diseases discussed in the chapter are summarized in Table 31.5.REVIEW QUESTIONS—CHAPTER 31

1.Which one of the following is involved in the synthesis of triacylglycerols in adipose tissue?

A. Fatty acids obtained from chylomicrons and VLDL B. Glycerol 3-P derived from blood glycerol

C. 2-Monoacylglycerol as an obligatory intermediate D. LPL to catalyze the formation of ester bonds

E. Acetoacetyl-CoA as an obligatory intermediate

2.A molecule of palmitic acid, attached to carbon 1 of the glycerol moiety of a triacylglycerol, is

A.VLDL

B.Chylomicron

C.Fatty acid–albumin complex

D.Bile salt micelle

E.LDL

3.A patient with hyperlipoproteinemia would be most likely to benefit from a low-carbohydrate diet if

the lipoproteins that are elevated in blood are which of the following? A. ChylomicronsB. VLDL

C. HDL D. LDL E. IDL

4.Patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency exhibit fasting

hypoglycemia for several reasons. In such patients, under fasting conditions, which one of the

following enzymes may not be fully activated, thus leading to an inability to carry out

gluconeogenesis?

A. Glucose 6-phosphatase B. Pyruvate carboxylase

C. Fructose 1,6-bisphosphatase

D. Phosphoenolpyruvate carboxykinase

E. Glyceraldehyde 3-phosphate dehydrogenase

5.Newly synthesized fatty acids are not immediately degraded because of which one of the following?

A. Tissues that synthesize fatty acids do not contain the enzymes that degrade fatty acids.

B. High NADPH levels inhibit β-oxidation.

C. In the presence of insulin, the key fatty acid–degrading enzyme is not induced. D. Newly synthesized fatty acids cannot be converted to their CoA derivatives.

E. Transport of fatty acids into mitochondria is inhibited under conditions in which fatty acids are

being synthesized.

6.In humans, prostaglandins are derived primarily from which one of the following? A. Glucose

B. Acetyl-CoA

C. Arachidonic acid D. Oleic acid

E. Leukotrienes

7.Individuals with a defect in glucose 6-phosphate dehydrogenase produce NADPH for the synthesis

of fatty acids owing to the presence of which one of the following enzymes? A. Malic enzyme

B. Fatty acid synthase C. Acetyl-CoA carboxylase D. C9-desaturase

E. Citrate lyase

8.Which one of the following drugs leads to the covalent modification, and inactivation, of both the

COX-1 and COX-2 enzymes? A. Aspirin

B. Acetaminophen (Tylenol) C. Celecoxib (Celebrex) D. Rofecoxib (Vioxx)

E. Ibuprofen (Advil)

9.Dietary fatty acids are precursors for sphingolipids. Of the following, which one is formed fromsphingolipids?

A. Lung surfactant B. Myelin sheath

C.Bile

D.Arachidonic acid

E.Blood lipoproteins

10. Low-dose aspirin is used as a prevention of platelet aggregation and heart attacks, whereas highdose aspirin is used as an antiinflammatory drug. Low-dose aspirin is used to block the formation of

which eicosanoid?

A.Prostaglandins

B.Thromboxanes

C.Leukotrienes

D.Lysoxins

E.Epoxides

ANSWERS TO REVIEW QUESTIONS

1.The answer is A. Fatty acids, cleaved from the triacylglycerols of blood lipoproteins by the

action of LPL, are taken up by adipose cells and react with coenzyme A to form fatty acyl-CoA.

Glucose is converted via DHAP to glycerol 3-P, which reacts with fatty acyl-CoA to form

phosphatidic acid (adipose tissue lacks glycerol kinase, so it cannot use glycerol directly). After

inorganic phosphate is released from phosphatidic acid, the resulting diacylglycerol reacts with

another fatty acyl-CoA to form a triacylglycerol, which is stored in adipose cells (2-

monoacylglycerol is an intermediate of triglyceride synthesis only in the intestine, not in adipose

tissue).

2.The answer is D. The triacylglycerol is degraded by pancreatic lipase, which releases the fatty

acids at positions 1 and 3. The fatty acids released are then transported to the cell surface in a bile

salt micelle. The only exception are short-chain fatty acids (shorter than palmitic acid), which can

diffuse to the cell surface and enter the intestinal cell in the absence of micelle formation.

3.The answer is B. Dietary carbohydrate is converted to lipid in the liver and exported via VLDL.

Thus, a low-carbohydrate diet will reduce VLDL formation and reduce the hyperlipoproteinemia.

4.The answer is B. Pyruvate carboxylase is activated, within the mitochondria, by acetyl-CoA.

High acetyl-CoA will also inhibit PDH, thereby allowing the pyruvate produced to be used for

gluconeogenesis, and not energy production. In MCAD, fatty acids are not fully oxidized (thereby

reducing the amount of energy available for gluconeogenesis), and acetyl-CoA levels do not reach

a point at which pyruvate carboxylase can be fully activated, thereby reducing precursor levels

available for gluconeogenesis. Glucose 6-phosphatase activity is not affected by acetyl-CoA

levels, nor is phosphoenolpyruvate carboxykinase activity (which is regulated at a transcriptional

level) or fructose 1,6-bisphosphatase activity (which is inhibited by fructose 2,6-bisphosphate).

Glyceraldehyde 3-phosphate is not a regulated enzyme of glycolysis or gluconeogenesis.

5.The answer is E. When fatty acids are being synthesized, malonyl-CoA accumulates, which

inhibits carnitine:palmitoyltransferase I. This blocks fatty acid entry into the mitochondrion foroxidation. Many tissues both synthesize and degrade fatty acids (such as liver and muscle; thus, A

is incorrect). NADPH blocks the glucose 6-phosphate dehydrogenase reaction, but not fatty acid

oxidation (thus, B is incorrect). Insulin has no effect on the synthesis of the enzymes involved in

fatty acid degradation (unlike the effect of insulin on the induction of enzymes involved in fatty

acid synthesis; thus, C is incorrect). Finally, newly synthesized fatty acids are converted to their

CoA derivatives for elongation and desaturation (thus, E is incorrect).

6.The answer is C. Most prostaglandins are synthesized from arachidonic acid (cis-Δ5,8,11,14

C20:4), which is derived from the essential fatty acid linoleic acid (cis-Δ9,12 C18:2). Glucose,

oleic acid, or acetyl-CoA cannot give rise to linoleic or arachidonic acid, as mammals cannot

introduce double bonds six carbons from the ω-end of a fatty acid. Leukotrienes are also derived

from arachidonic acid, but they are not precursors of prostaglandins; they follow a different

pathway.

7.The answer is A. Fatty acid synthesis requires NADPH, which can be generated by the hexose

monophosphate shunt pathway or by malic enzyme activity. In the absence of glucose 6-phosphate

dehydrogenase activity, malic enzyme, along with a mitochondrial transhydrogenase, would

provide the NADPH for fatty acid biosynthesis. Cytosolic isocitrate dehydrogenase can also

produce NADPH under these conditions. Neither the fatty acid synthase, citrate lyase, C9-

desaturase, or acetyl-CoA carboxylase generate NADPH.

8.The answer is A. Aspirin leads to the acetylation of COX-1 and COX-2, which inhibits the

enzymes. Tylenol contains acetaminophen, which is a competitive inhibitor of both COX-1 and

COX-2, but acetaminophen does not attach covalently to the enzymes. Advil contains ibuprofen,

which is another competitive inhibitor of the COX enzymes. Vioxx and Celebrex contain inhibitors

that are specific for COX-2, which is the form of cyclooxygenase that is induced during

inflammation. Vioxx and Celebrex do not inhibit COX-1 activity.

9.The answer is B. Sphingolipids are important in signal transduction and the formation of myelin

sheaths of the central nervous system. Glycerophospholipids are components of blood lipoproteins, bile, and lung surfactant. Arachidonic acid is a polyunsaturated fatty acid required

for signal transduction, but it is not formed from a sphingolipid.

10.The answer is B. Aspirin irreversibly inhibits cyclooxygenase which produces prostaglandins

and thromboxanes. Thromboxanes are in platelets and inhibition of their aggregation reduces

clotting which can prevent a heart attack. Prostaglandins are involved in inflammation.

Leukotrienes and lipoxins are produced by lipoxygenase and epoxides by a chromosome P450

system.32

Cholesterol Absorption, Synthesis, Metabolism, and Fate

For additional ancillary materials related to this chapter, please visit thePoint. Cholesterol is one of the most well-recognized molecules in human biology, in part because of the direct

relationship between its concentrations in blood and tissues and the development of atherosclerotic

vascular disease. Cholesterol, which is transported in the blood in lipoproteins because of its absolute

insolubility in water, serves as a stabilizing component of cell membranes and as a

precursor of the bile

salts and steroid hormones. Precursors of cholesterol are converted to ubiquinone, dolichol, and, in the

skin, to cholecalciferol, the active form of vitamin D. As a major component of blood lipoproteins,

cholesterol can appear in its free, unesterified form in the outer shell of these macromolecules and as

cholesterol esters in the lipoprotein core.

Cholesterol is obtained from the diet or synthesized by a pathway that occurs in most cells of the body

but to a greater extent in cells of the liver and intestine. The precursor for cholesterol synthesis is acetyl

coenzyme A (acetyl-CoA), which can be produced from glucose, fatty acids, or amino acids. Two

molecules of acetyl-CoA form acetoacetyl coenzyme A (acetoacetyl-CoA), which condenses with

another molecule of acetyl-CoA to form hydroxymethylglutaryl coenzyme A (HMG-CoA). Reduction

of HMG-CoA produces mevalonate. This reaction, catalyzed by HMG-CoA reductase, is the major

rate-limiting step of cholesterol synthesis. Mevalonate produces isoprene units that condense, eventually

forming squalene. Cyclization of squalene produces the steroid ring system, and several subsequent

reactions generate cholesterol. The adrenal cortex and the gonads also synthesize cholesterol in

significant amounts and use it as a precursor for steroid hormone synthesis. Cholesterol is packaged in chylomicrons in the intestine and in very-low-density lipoprotein

(VLDL) in the liver. It is transported in the blood in these lipoprotein particles, which also transport

triacylglycerols. As the triacylglycerols of the blood lipoproteins are digested by lipoprotein lipase

(LPL), chylomicrons are converted to chylomicron remnants, and VLDL is converted to intermediatedensity lipoprotein (IDL) and subsequently to low-density lipoprotein (LDL). These products return tothe liver, where they bind to receptors in cell membranes and are taken up by endocytosis and digested by

lysosomal enzymes. LDL is also endocytosed by nonhepatic (peripheral) tissues. Cholesterol and other

products of lysosomal digestion are released into the cellular pools. The liver uses this recycled

cholesterol, and the cholesterol that is synthesized from acetyl-CoA, to produce VLDLand to synthesize

bile salts.

Intracellular cholesterol obtained from blood lipoproteins decreases the synthesis of cholesterol

within cells, stimulates the storage of cholesterol as cholesterol esters, and decreases the synthesis of

LDL receptors. LDL receptors are found on the surface of the cells and bind various classes of

lipoproteins before endocytosis.

Although high-density lipoprotein (HDL) contains triacylglycerols and cholesterol, its function is

very different from that of the chylomicrons and VLDL, which transport triacylglycerols. HDL exchanges

proteins and lipids with the other lipoproteins in the blood. HDLtransfers apolipoprotein E (apoE) and

apolipoprotein CII (apoCII) to chylomicrons and VLDL. After digestion of the VLDLtriacylglycerols,

apoE and apoCII are transferred back to HDL. In addition, HDL obtains cholesterol from other

lipoproteins and from cell membranes and converts it to cholesterol esters by the lecithin–cholesterol

acyltransferase (LCAT) reaction. Then, HDL either directly transports cholesterol and cholesterol

esters to the liver or transfers cholesterol esters to other lipoproteins via the cholesterol ester transfer

protein (CETP). Ultimately, lipoprotein particles carry the cholesterol and cholesterol esters to the liver,

where endocytosis and lysosomal digestion occur. Thus, reverse cholesterol transport (i.e., the return of

cholesterol to the liver) is a major function of HDL.

Elevated levels of cholesterol in the blood are associated with the formation of atherosclerotic

plaques that can occlude blood vessels, causing heart attacks and strokes. Although high levels of LDL

cholesterol are especially atherogenic, high levels of HDLcholesterol are protective because HDL

particles are involved in the process of removing cholesterol from tissues, such as the lining cells of

vessels, and returning it to the liver.

Bile salts, which are produced in the liver from cholesterol obtained from the blood lipoproteins or

synthesized from acetyl-CoA, are secreted into the bile. They are stored in the gallbladder and released

into the intestine during a meal. The bile salts emulsify dietary triacylglycerols, thus aiding in digestion.

The digestive products are absorbed by intestinal epithelial cells from bile salt micelles, tiny

microdroplets that contain bile salts at their water interface. After the contents of the micelles are

absorbed, most of the bile salts travel to the ileum, where they are resorbed and recycled by the liver.

Less than 5% of the bile salts that enter the lumen of the small intestine are eventually excreted in the

feces.

Although the fecal excretion of bile salts is relatively low, it is a major means by which the body

disposes of the steroid nucleus of cholesterol. Because the ring structure of cholesterol cannot be

degraded in the body, it is excreted mainly in the bile as free cholesterol and bile salts.

The steroid hormones, derived from cholesterol, include the adrenal cortical hormones (e.g., cortisol,

aldosterone, and the adrenal sex steroids dehydroepiandrosterone [DHEA] and androstenedione) and the

gonadal hormones (e.g., the ovarian and testicular sex steroids, such as testosterone and estrogen).

THE WAITING ROOMAt his next office visit, Ivan A.’s case was reviewed by his physician. Mr. A. has several of the

major risk factors for coronary heart disease. These include a sedentary lifestyle, marked obesity,

hypertension, hyperlipidemia, and early type 2 diabetes. Unfortunately, he has not been able to follow his

doctor’s advice with regard to a diabetic diet designed to effect a significant loss of weight, nor has he

followed an aerobic exercise program. As a consequence, his weight has gone from 270 to 291 lb. After a

14-hour fast, his serum glucose is now 214 mg/dL(normal, <100 mg/dL), and his serum total cholesterol

level is 314 mg/dL(according to recent guidelines, the LDLcholesterol value has an upper limit but not

total cholesterol). His serum triacylglycerol level is 295 mg/dL(desired level is 150 mg/dLor less), and

his serum HDLcholesterol is 24 mg/dL(desired level is ≥40 mg/dLfor a man). His calculated serum LDL

cholesterol level is 231 mg/dL(when LDLcholesterol is >190 mg/dL, treatment is strongly recommended

to help prevent cardiovascular disease). Mr. A. exhibits sufficient criteria to be classified as having